RESEARCH ARTICLE
A facile access and evaluation of some
novel thiazole and 1,3,4-thiadiazole derivatives
incorporating thiazole moiety as potent
anticancer agents
Sobhi M. Gomha
1*, Mohamad R. Abdelaziz
2, Nabila A. Kheder
1,3, Hassan M. Abdel‑aziz
4, Seham Alterary
5and Yahia N. Mabkhot
5*Abstract
Background: Many heterocyclic compounds containing thiazole or 1,3,4‑thiadiazole ring in their skeletons have been reported to possess various pharmacological activities especially anticancer activities.
Results: 4‑Methyl‑2‑phenylthiazole‑5‑carbohydrazide (2) was used as a synthon to prepare 2‑(4‑methyl‑2‑phe‑ nylthiazole‑5‑carbonyl)‑N‑phenylhydrazinecarbothioamide (3) and 2‑(2‑(4‑methyl‑2‑phenylthiazole‑5‑carbonyl) hydrazono)‑N′‑phenylpropane hydrazonoyl chlorides 5a–c. In addition, thioamide 3 was used as starting material for preparation of a new series of thiadiazole derivatives via its reaction with hydrazonoyl chlorides 5a–c in dioxane using triethylamines as catalyst. In addition, a series of thiazole derivatives was synthesized by reaction of thioamide 3 with a number of α‑halo compounds, namely, 3‑chloropentane‑2,4‑dione (8) or 2‑chloro‑3‑oxo‑N‑phenyl butanamide (10) phenacyl bromide 12 ethyl chloroacetate (14) in EtOH in the presence of triethylamine. The structures assigned for all the new products were elucidated based on both elemental analyses and spectral data and the mechanisms of their formation was also discussed. Moreover, the new products was evaluated in vitro by MTT assays for their anticancer activity against cell lines of Hepatocellular carcinoma cell line (HepG‑2). The best result observed for compounds 7b (IC50= 1.61 ± 1.92 (μg/mL)) and 11 (IC50= 1.98 ± 1.22 (μg/mL)). The structure–activity relationships have been sug‑ gested based on their anticancer results.
Conclusions: A novel series of new pharmacophores containing thiazole moiety have been synthesized using a facile and convenient methods and evaluated as potent anticancer agents.
Keywords: Thiazoles, Thiadiazoles, Hydrazonoyl chlorides, Phenacyl bromide, Thioamide, Anticancer activity
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Open Access
*Correspondence: [email protected]; [email protected]
1 Department of Chemistry, Faculty of Science, Cairo University,
Giza 12613, Egypt
5 Department of Chemistry, College of Science, King Saud University, P. O.
Box 2455, Riyadh 11451, Saudi Arabia
Full list of author information is available at the end of the article Introduction
Identification of novel structure leads that may be of use in designing new, potent, selective and less toxic antican-cer agents remains a major challenge for medicinal chem-istry researchers. Compounds containing thiazole core have diverse biological activities as antihypertension,
antifungal, antimicrobial, anti-inflammatory, antioxi-dant, antitubercular [1–7], and anticancer [8–12]. Also, thiazole ring present in many drugs such as Nizatidine, Abafungin, and Amiphenazole (Fig. 1).
In continuation of our studies dealing with the utility of hydrazonoyl halides for synthesis of various bioactive bridgehead nitrogen polyheterocycles [21–30], we wish to report herein a new facile synthesis of new heterocy-cles containing thiazole and 1,3,4-thiadiazole or two thia-zole rings in one molecular frame. We anticipated that the synthesized compounds would have potent pharma-cological activities.
Results and discussion
Chemistry
2-(4-Methyl-2-phenylthiazole-5-carbonyl)-N -phenylhy-drazinecarbothioamide (3) [31] was prepared via reaction
of 4-methyl-2-phenylthiazole-5-carbohydrazide (2) with phenyl isothiocyanate in EtOH (Scheme 1).
The reaction of compound 2 with the appropri-ate hydrazonoyl chlorides 4a–c [32] in refluxing etha-nol yielded the corresponding condensation product 5 (Scheme 2). The IR spectra of the latter products revealed a carbonyl and two NH absorption bands (see “Experimental” part). Their 1HNMR showed two D
2O
exchangeable signals of two NH protons in the regions δ 10.03–10.06 and δ 10.57–10.59 ppm. Also, their mass spectra confirmed the assigned structure 5 (Scheme 2). Treatment of thioamide derivative 3 with the appropri-ate hydrazonoyl halides of type 5a–c in refluxing EtOH
Fig. 1 Some marketed drugs containing thiazole ring
Fig. 2 Examples of drugs containing a 1,3,4‑thiadiazole ring
S N
Ph O
NH HN CH3 HN
S
Ph PhNCS / EtOH
S N
Ph
O OEt
CH3 NH2NH2.H2O
1 2
S N
O N H
NH2 Ph
CH3
3
containing TEA gave the corresponding thiadiazole derivatives 7a–c (Scheme 2). Their structures were elu-cidated on the basis of their spectral data and elemental analysis (see “Experimental”).
Next, refluxing of compound 3 with 3-chloropentane-2,4-dione (8) or 2-chloro-3-oxo-N-phenyl butanamide (10) in EtOH in the presence of triethylamine afforded the thia-zole derivatives 9 and 11, respectively (Scheme 3).The struc-ture of compounds 9 and 11 were elucidated based on their elemental analysis and spectral data (see “Experimental”).
In a similar manner, thioamide 3 reacted with phenacyl bromide 12 under the same experimental condition to afford one isolable product 13 named as N′-(3,4-diphenylthiazol- 2(3H)-ylidene)-4-methyl-2-phenyl thiazole-5-carbohydrazide (Scheme 3). The structure of thiazole 13 was established based on its elemental analysis and spectral data (see “Experimental”).
Finally, thioamide derivative 3 reacted with ethyl chloroacetate (14) to afford thiazole 15 as showed in Scheme 3. Its IR spectrum showed absorption bands at v 3331 (NH), and 1726, 1648 (2C=O) cm−1. In addition,
its 1HNMR spectrum showed singlet signal at δ 4.23 ppm
due to the thiazolidinone (CH2) group.
Anticancer activity
The synthesized compounds were tested as antican-cer agents against human Hepatocellular carcinoma cell line (HepG-2) using colorimetric MTT assay. We also included the well-known anticancer standard drug
(Cisplatin) in the same assay to compare the potency of the synthesized compounds. The IC50 (the concentration
of test compounds required to kill 50% of cell population) was determined (Table 1, Fig. 3).
The results of Table 1 revealed that the ascending order of the cytotoxic activity of the newly synthesized com-pounds towards the human Hepatocellular carcinoma cell line (HepG-2) were as follow: 5c < 13 < 5a < 5b < 9 < 7c < 15 < 7a < 11 < 7b (Fig. 4).
From the data of Table 1, we concluded the following structure–activity relationships (SARs):
• The thiazole ring is essential for the activity.
• Less number of thiazole ring as in compounds 5a–c lead to drastic drop in activity.
• 1,3,4-Thiadiazole ring is crucial for the cytotoxic activity.
• Presence of methyl group (electron donating group) at position 4 of the phenyl ring in compound 7b increase its activity more than compound 7a.
• The presence of the N-phenylcarboxamide group in compound 11 leads to increasing of its cytotoxic activity.
Experimental
Chemistry General
Melting points were measured on an Electrothermal IA 9000 series digital melting point apparatus (Bibby Sci.
Lim. Stone, Staffordshire, UK). IR spectra were meas-ured on PyeUnicamSP 3300 and Shimadzu FTIR 8101 PC infrared spectrophotometers (Shimadzu, Tokyo, Japan) in potassium bromide discs. NMR spectra were meas-ured on a Varian Mercury VX-300 NMR spectrometer (Varian, Inc., Karlsruhe, Germany) operating at 300 MHz (1HNMR) and run in deuterated dimethylsulfoxide
(DMSO-d6). Chemical shifts were related to that of the solvent. Mass spectra were recorded on a Shimadzu GCMS-QP1000 EX mass spectrometer (Tokyo, Japan) at 70 eV. Elemental analyses were measured by using a German made Elementarvario LIII CHNS analyzer. 2-(4-Methyl-2-phenylthiazole-5-carbonyl)-N -phenylhy-drazinecarbothioamide (3) [31], and hydrazonoyl halides 4a–c [32] were prepared as reported in the respective literature.
Synthetic procedures
Synthesis of hydrazonoyl chlorides 5a–c
A mixture of 4-methyl-2-phenylthiazole-5-carbohy-drazide (2) (2.33 g, 10 mmol) and the appropriate hydra-zonoyl chlorides 4a–c (10 mmol) in ethanol (30 mL) was refluxed for 3–5 h (monitored through TLC).The result-ing solid product was collected and recrystallized from the proper solvent to give the corresponding products 5a–c.
2‑(2‑(4‑Methyl‑2‑phenylthiazole‑5‑carbonyl)hydrazono)‑ N′‑phenylpropane hydrazonoyl chloride (5a) Yellow solid; yield (84%); m.p. 188–190 °C (EtOH); IR (KBr) v 3440, 3316 (2NH), 3036, 2922 (CH), 1640 (C=O), 1599 (C=N) cm−1; 1H NMR (DMSO-d
6) δ 2.36 (s, 3H, CH3), 2.76 (s, 3H, CH3), 7.06–7.86 (m, 10H, ArH), 10.03
(s, br, 1H, D2O-exchangeable NH), 10.57 (s, br, 1H,
D2O-exchangeable NH); MS m/z (%): 413 (M++2, 12),
411 (M+, 40), 375 (48), 202 (100), 174 (45), 71 (26). Anal.
Calcd for C20H18ClN5OS (411.91): C, 58.32; H, 4.40; N,
17.00. Found: C, 58.19; H, 4.37; N, 16.88%.
2‑(2‑(4‑Methyl‑2‑phenylthiazole‑5‑carbonyl)hydrazono)‑ N′‑(p‑tolyl)propane‑ hydrazonoylchloride (5b) Yellow solid; yield (86%); m.p. 172–174 °C (EtOH); IR (KBr) v 3437, 3313 (2NH), 3041, 2917 (CH), 1679 (C=O), 1598 (C=N) cm−1; 1H NMR (DMSO-d
6) δ 2.24 (s, 3H, CH3),
2.34 (s, 3H, CH3), 2.77 (s, 3H, CH3), 7.08–7.99 (m, 9H,
ArH), 10.06 (s, br, 1H, D2O-exchangeable NH), 10.59 (s,
br, 1H, D2O-exchangeable NH); MS m/z (%) 427 (M++2, EtOH / TEA
3 13 9 11 15 Cl CONHPh COCH3 Cl COCH3 COCH3 Cl COOEt Br COPh S N Ph O H N N CH3 N
S Ph Ph S N Ph O H N N CH3 N
S COCH3
Ph
CH3 EtOH / TEA EtOH / TEA
EtOH / TEA S N Ph O H N N CH3 N
S CONHPh
Ph
CH3 S
N Ph
O H
N N CH3 N
S Ph O 14 12 10 8 S N Ph O H N N H CH3 N H S Ph - HCl, -H2O - HBr, -H2O
- HCl, -EtOH - HCl, -H2O
Scheme 3 Synthesis of thiazole derivatives 9, 11, 13 and 15
Table 1 The in vitro inhibitory activity of the tested com-pounds against tumor cell lines expressed as IC50 values (μg/mL) ± standard deviation from three replicates
Tested
compounds IC50 (μg/mL) Tested compounds IC50 (μg/mL)
Cisplatin 1.43 ± 2.03 7c 7.51 ± 0.64
5a 22.3 ± 2.41 9 17.4 ± 0.73
5b 20.3 ± 3.70 11 1.98 ± 1.22
5c 57.2 ± 7.12 13 35.1 ± 10.8
7a 2.14 ± 3.54 15 3.31 ± 2.65
10), 425 (M+, 33), 389 (26), 202 (81), 106 (100), 64 (66).
Anal. Calcd for C21H20ClN5OS (425.93): C, 59.22; H, 4.73;
N, 16.44. Found: C, 59.18; H, 4.65; N, 16.37%.
N′‑(4‑Chlorophenyl)‑2‑(2‑(4‑methyl‑2‑phenylthiazole ‑5‑carbonyl)hydrazono) propane hydrazonoyl chloride (5c) Yellow solid; yield (87%); m.p. 194–196 °C (DMF); IR (KBr) v 3434, 3319 (2NH), 3044, 2926 (CH), 1682 (C=O), 1593 (C=N) cm−1; 1H NMR (DMSO-d
6) δ 2.37 (s, 3H, CH3), 2.77 (s, 3H, CH3), 7.08–7.99 (m, 9H, Ar–H),
10.06 (s, br, 1H, D2O-exchangeable NH), 10.57 (s, br, 1H,
D2O-exchangeable NH); MS m/z (%) 446 (M+, 8), 283
(14), 202 (39), 104 (46), 80 (100), 64 (90). Anal. Calcd for C20H17Cl2N5OS (446.35): C, 53.82; H, 3.84; N, 15.69.
Found: C, 53.75; H, 3.79; N, 15.58%.
Synthesis of 1,3,4‑thiadiazole derivatives 7a–c
A mixture of compound 3 (0.368 g, 1 mmol) and the appropriate hydrazonoyl chlorides 5a–c (1 mmol) in ethanol (20 mL) containing triethylamine (0.1 g, 1 mmol) was refluxed for 6 h. The formed solid product was fil-tered, washed with methanol, dried and recrystallized from the suitable solvents to give corresponding prod-ucts 7a–c.
4‑Methyl‑N′‑(1‑(‑5‑(2‑(4‑methyl‑2‑phenylthiazole‑5‑ carbonyl)hydrazono)‑4‑phenyl‑4,5‑dihydro‑1,3,4‑thi‑ adi a z ol‑2‑ yl)ethylidene)‑2‑phenylthi a z ole‑5‑
carbohydrazide(7a) Yellow solid; yield (74%); m.p.
162–164 °C (EtOH); IR (KBr) v 3421, 3307 (2NH), 3031, 2951 (CH), 1649 (C=O), 1596 (C=N) cm−1;
0 10 20 30 40 50 60
IC50
values
Fig. 3 Comparison of the IC50 of the new synthesized compounds against Cisplatin
11 15
Ar HN
N N
S CONHPh
Ph CH3 Ar HNN
N S
Ph O
Ar
HN N N N
S H3C
N HN
Ar
Ar
HN N N N S H3C
N HN
Ar
7a 7b
IC50 = 2.14 ± 3.54µg/mL IC50 = 1.98 ± 1.22µg/mL IC50= 1.61 ± 1.92µg/mL
IC50 = 3.31 ± 2.65µg/mL
CH3
Increasing order of cytotoxic activity Ar =
O S N
CH3 Ph
Cisplatin
IC50 =1.43±2.03
1H NMR (DMSO-d
6) δ 2.34 (s, 3H, CH3), 2.66 (s, 3H,
CH3), 2.76(s, 3H, CH3), 6.97-8.14 (m, 15H, ArH), 10.18
(s, br, 1H, D2O-exchangeable NH), 11.17 (s, br, 1H,
D2O-exchangeable NH); MS m/z (%) 650 (M+, 34), 526
(30), 416 (60), 358 (28), 104 (55), 64 (100). Anal. Calcd for C32H26N8O2S3 (650.80): C, 59.06; H, 4.03; N, 17.22. Found
C, 58.94; H, 4.01; N, 17.07%.
4‑Methyl‑N′‑(1‑(5‑(2‑(4‑methyl‑2‑phenylthiazole‑5‑c arbonyl)hydrazono)‑4‑(p‑tolyl)‑4,5‑dihydro‑1,3,4‑thi‑ adiazol‑2‑yl)ethylidene)‑2‑phenylthiazole‑5‑carbohy‑ drazide (7b) Yellow solid; yield (72%); m.p. 149–151 °C (EtOH); IR (KBr) v 3422, 3328 (2NH), 3053, 2929 (CH), 1647 (C=O), 1597 (C=N) cm−1; 1H NMR (DMSO-d6) δ 2.26 (s, 3H, CH3),2.35 (s, 3H, CH3), 2.65 (s, 3H,
CH3), 2.76(s, 3H, CH3), 6.91–8.03 (m, 14H, ArH), 10.18
(s, br, 1H, D2O-exchangeable NH), 11.14 (s, br, 1H,
D2O-exchangeable NH); MS m/z (%) 664 (M+, 35), 553
(60), 334 (19), 202 (65), 104 (85), 64 (100). Anal. Calcd for C33H28N8O2S3 (664.82): C, 59.62; H, 4.25; N, 16.85. Found
C, 59.47; H, 4.17; N, 16.79%.
N′‑(3‑(4‑Chlorophenyl)‑5‑(1‑(2‑(4‑methyl‑2‑phenylt hiazole‑5‑carbonyl)hydrazono)eth‑yl)‑1,3,4‑thiadia‑ zol‑2(3H)‑ylidene)‑4‑methyl‑2‑phenylthiazole‑5‑carbohy‑ drazide (7c) Yellow solid; yield (76%); m.p. 191–193 °C (Dioxane); IR (KBr) v 3424, 3312 (2NH), 3047, 2932 (CH), 1649 (C=O), 1599 (C=N) cm−1; 1H NMR (DMSO-d
6) δ 2.33 (s, 3H, CH3), 2.66 (s, 3H, CH3), 2.77(s, 3H, CH3), 6.90–
8.11 (m, 14H, ArH), 10.13 (s, br, 1H, D2O-exchangeable
NH), 11.19 (s, br, 1H, D2O-exchangeable NH); MS m/z
(%) 686 (M++2, 8), 684 (M+, 26), 513 (53), 368 (39), 257
(17), 104 (25), 64 (100). Anal.Calcd for C32H25ClN8O2S3
(685.24): C, 56.09; H, 3.68; N, 16.35. Found C, 56.02; H, 3.58; N, 16.22%.
General procedure for the synthesis of thiazole derivatives 9, 11, 13, and 15
A mixture of compound 3 (0.368 g, 1 mmol) and the appropriate α-halo-compounds namely, 3-chloropen-tane-2,4-dione (8), 2-chloro-3-oxo-N-phenylbutanamide (10), 2-bromo-1-phenyl ethanone (12) and ethyl 2-chlo-roacetate (14) (1 mmol for each) in ethanol (20 mL) con-taining triethylamine (0.1 g, 1 mmol) was refluxed for 4–6 h. (monitored by TLC The solid product was filtered, washed with water, dried and recrystallized from the proper solvent to give the corresponding thiazole deriva-tives 9, 11, 13, and 15, respectively.
N′‑(5‑Acetyl‑4‑methyl‑3‑phenylthiazol‑2(3H)‑ylidene)‑4 ‑methyl‑2‑phenylthiazole‑5‑carbohydrazide (9) Yellow solid; yield (78%); m.p. 155–157 °C (EtOH); IR (KBr) v 3432
(NH), 3036, 2993 (CH), 1695, 1648 (2C=O), 1590 (C=N) cm−1; 1H NMR(DMSO-d
6) δ 2.32 (s, 3H, CH3),2.46 (s, 3H,
CH3), 2.77 (s, 3H, CH3), 6.91–7.86 (m, 10H, ArH), 10.61
(s, br, 1H, D2O-exchangeable NH); MS m/z (%) 448 (M+,
57), 246 (60), 176 (35), 104 (80), 77 (100). Anal.Calcd for C23H20N4O2S2 (448.56): C, 61.59; H, 4.49; N, 12.49. Found
C, 61.48; H, 4.36; N, 12.37%.
4‑Methyl‑2‑(2‑(4‑methyl‑2‑phenylthiazole‑5‑carbonyl) hydrazono)‑N‑3‑diphenyl‑2,3‑dihydrothiazole‑5‑carbox‑ amide (11) Yellow solid; yield (79%); m.p. 182–84 °C (DMF); IR (KBr): v 3435, 3176 (2NH), 3030, 2928(CH), 1671, 1649 (2C=O), 1594 (C=N) cm−1; 1H NMR (DMSO-d6) δ 2.36 (s, 3H, CH3),2.76(s, 3H, CH3), 6.97–7.73 (m,
15H, ArH), 10.46 (s, br, 1H, D2O-exchangeable NH), 11.72
(s, br, 1H, D2O-exchangeable NH); MS m/z (%) 525 (M+,
7), 447 (16), 334 (100), 200 (59), 77 (89). Anal.Calcd for C28H23N5O2S2 (525.64): C, 63.98; H, 4.41; N, 13.32. Found
C, 63.84; H, 4.30; N, 13.28%.
N′‑(3,4‑Diphenylthiazol‑2(3H)‑ylidene)‑4‑methyl‑2‑ph enylthiazole‑5‑carbohydrazide (13) Yellow solid; yield (70%); m.p. 174–178 °C (EtOH); IR (KBr) v 3369 (NH), 3047, 2926(CH), 1648 (C=O), 1594 (C=N) cm−1; 1H
NMR (DMSO-d6) δ 2.75 (s, 3H, CH3), 7.03 (s, 1H,
thi-azole-H5), 7.35–8.02 (m, 15H, ArH), 10.73 (s, br, 1H, D2O-exchangeable NH); MS m/z (%) 468 (M+, 25),
334 (100), 200 (40), 104 (69), 64(65). Anal.Calcd for C26H20N4OS2 (468.59): C, 66.64; H, 4.30; N, 11.96. Found
C, 66.55; H, 4.21; N, 11.79%.
4‑Methyl‑N′‑(4‑oxo‑3‑phenylthiazolidin‑2‑ylidene)‑2‑p henylthiazole‑5‑carbo‑ hydrazide (15) Yellowish-white solid; yield (72%); m.p. 192–194 °C (Dioxane); IR (KBr) v 3331(NH), 3036, 2926 (CH), 1726, 1648 (2C=O), 1596 (C=N) cm−1; 1H NMR (DMSO-d
6) δ 2.65 (s, 3H, CH3),
4.23 (s, 2H, thiazolone-CH2), 7.40–7.88 (m, 10H, ArH),
10.82 (s, br, 1H, D2O-exchangeable NH); MS m/z (%) 408
(M+, 65), 334 (18), 202 (100), 104 (86), 64 (69). Anal.Calcd
for C20H16N4O2S2 (408.50): C, 58.80; H, 3.95; N, 13.72.
Found C, 58.68; H, 3.84; N, 13.64%.
Anticancer activity
The cytotoxic evaluation of the synthesized compounds was carried out at the Regional Center for Mycology and Biotechnology at Al-Azhar University, Cairo, Egypt according to the reported method [33].
Conclusions
prepared compounds was established based on both ele-mental analysis and spectroscopic data. The anticancer activity of the synthesized compounds was measured and showed promising activity.
Abbreviations
HepG2: human hepatocellular carcinoma; EtOH: ethanol; m.p.: melting point; TEA: triethylamine; IR: infra‑red; ATCC: American Type Culture Collection; TLC: thin layer chromatography.
Authors’ contributions
SMG, NAK and YNM carried the literature study and designed synthetic schemes, MRA and SA contributed in the synthesis and purification of the compounds. All authors read and approved the final manuscript.
Author details
1 Department of Chemistry, Faculty of Science, Cairo University, Giza 12613,
Egypt. 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, MIU
University, Cairo, Egypt. 3 Department of Pharmaceutical Chemistry, Faculty
of Pharmacy, King Khalid University, Abha 61441, Saudi Arabia. 4 Department
of Chemistry, Faculty of Science, University of Beni Suef, Beni Suef, Egypt.
5 Department of Chemistry, College of Science, King Saud University, P. O.
Box 2455, Riyadh 11451, Saudi Arabia.
Acknowledgements
The authors extend their sincere appreciation to the Deanship of Scientific Research at the King Saud University for its funding this Prolific Research group (PRG‑1437‑29).
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub‑ lished maps and institutional affiliations.
Received: 16 July 2017 Accepted: 10 October 2017
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20. Gomha SM, Badrey MG, Edrees MM (2016) Heterocyclization of a bis‑thio‑ semicarbazone of 2,5‑diacetyl‑3,4‑disubstituted‑thieno[2,3‑b]thiophene bis‑thiosemicarbazones leading to bis‑thiazoles and bis‑1,3,4‑thiadiazoles as anti‑breast cancer agents. J Chem Res 40:120–125
21. Gomha SM (2009) A facile one‑pot synthesis of 6,7,8,9‑tetrahydrobenzo [4,5]thieno [2,3‑d]‑1,2,4‑triazolo[4,5‑a]pyrimidin‑5‑ones. Monatsh Chem 140:213–220
22. Abdelhamid AO, Gomha SM, Abdelriheem NA (2017) Utility of 2‑(5‑met‑ hyl‑1‑phenyl‑1H‑pyrazol‑4‑yl)‑2‑oxo‑N′‑phenylaceto‑hydrazonoyl bro‑ mide as precursor for synthesis of new functionalized heterocycles. Synth Commun 47:999–1005
23. Abbas IM, Gomha SM, Elneairy MAA, Elaasser MM, Mabrouk BKA (2015) Synthesis and characterization of some novel fused thiazolo[3,2‑a]pyrimi‑ dinones and pyrimido[2,1‑b][1,3]thiazinones. J Chem Res 39:719–723 24. Gomha SM, Riyadh SM (2009) Synthesis of triazolo[4,3‑b][1,2,4,5]tetrazines
and triazolo[3,4‑b][1,3,4]thiadiazines using chitosan as ecofriendly cata‑ lyst under microwave irradiation. Arkivoc 11:58–68
25. Abdallah MA, Riyadh SM, Abbas IM, Gomha SM (2005) Synthesis and biological activities of 7‑arylazo‑7H‑pyrazolo[5,1‑c][1,2,4]triazolo‑6(5H)‑ ones and 7‑arylhydrazono‑7H‑[1, 2, 4]triazolo[3,4‑b][1,3,4]thiadiazines. J Chin Chem Soc 52:987–994
26. Gomha SM, Badrey MG, Abdalla MM, Arafa RK (2014) Novel Anti‑HIV‑1 NNRTIs Based on a pyrazolo[4,3‑d]isoxazole backbone scaffold: design, synthesis and exploration of molecular basis of action. Med Chem Com‑ mun 5:1685–1692
27. Abbas IM, Riyadh SM, Abdallah MA, Gomha SM (2006) A novel route to tetracyclic fused tetrazines and thiadiazines. J Heterocycl Chem 43:935–942
28. Dawood KM, Gomha SM (2015) Synthesis and anti‑cancer activity of 1,3,4‑thiadiazole and 1,3‑thiazole derivatives having 1,3,4‑oxadiazole moiety. J Heterocycl Chem 52:1400–1405
29. Gomha SM, Riyadh SM (2014) Multicomponent synthesis of novel penta‑ heterocyclic ring systems incorporating benzopyranopyridines scaffold. Synthesis 46:258–262
31. Tiperciuc B, Zaharia V, Colosi I, Moldovan C, Crişan O, Pîrnau A, Vlase L, Duma M, Oniga O (2012) Synthesis and evaluation of antimicrobial activ‑ ity of some new hetaryl‑azoles derivatives obtained from 2‑aryl‑4‑meth‑ ylthiazol‑5‑carbohydrazides and isonicotinic acid hydrazide. J Heterocycl Chem 49:1407–1414
32. Shawali AS, Gomha SM (2000) A New entry for short and regioselective synthesis of [1,2,4]triazolo[4,3‑b][1,2,4]‑triazin‑7(1H)‑one. Adv Synth Catal 342:599–604